Atorvastatin is a reductase inhibitor of the enzyme 3-hydroxy-3-methylglutarate-coenzyme A (HMG-CoA) and therefore is a useful anti-hyperlipoproteinemic agent. It has proven to be a highly effective medicament for the treatment of disorders such as hyperlipidemia and hypercholesterolemia which are conditions that are known risk factors for arteriosclerosis and coronary heart disease. Atorvastatin is chemically [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrole-1-heptanoic acid and is marketed as its calcium salt under the brand name Lipitor™.
A route to Atorvastatin (6) is taught in U.S. Pat. No. 5,273,995. Depicted in Scheme 1 herein is a sequence of reactions from the process taught in U.S. Pat. No. 5,273,995 involving the alkylation of aldehyde 1 to form the chiral ester 2 followed by transesterification to the methylester 3 using sodium methoxide. Methylester 3 is then reacted with the lithium enolate of tert-butylacetate to form the β-ketoester 5, which is then further reacted over a series of steps to form Atorvastatin Calcium (6). If scale-up of this transformation (2 to 5) were contemplated, then this route would suffer from serious deficiencies. These include:                a. purification of the β-hydroxy methylester 2 via silica gel column purification        b. no mention is made regarding the recovery of the expensive chiral auxiliary [(S)-1,1,2-triphenyl-1,2-ethanediol, 4]        c. the initial transesterification step employs the expensive, flammable and corrosive base sodium methoxide under anhydrous conditions        d. sodium methoxide is also a strong base which may lead to side reactions        e. the formation of the enolate of tert-butylacetate used in the formation of 5 is accomplished using lithium diisopropylamine which requires a separate preparative step and the use of diisopropylamine and n-butyllithium in THF at −40° C.        f. the reaction temperature required for the subsequent alkylation of the α-hydroxy methylester 3 with the lithium enolate of tert-butylacetate is very low (−70° C.)        g. example 3 of U.S. Pat. No. 5,273,995 requires the addition of the α-hydroxy methylester 3 in absolute THF to the lithium enolate solution “as quickly as possible without allowing the temperature to rise above −40° C.”.        

Thus, work was undertaken to overcome the deficiencies of the prior art and to provide a facile and commercially viable process, and to provide a method that would allow convenient recovery of the expensive chiral auxiliary 4 [(S)-1,1,2-triphenyl-1,2-ethanediol] in enantiomerically pure form. This permits re-use in the process after acetylation of the secondary hydroxyl group.